In a multicenter, randomized, double-blinded phase II trial of the Met inhibitor ARQ 197-207, conducted among more than 160 patients, ARQ appeared to give those with metastatic non-small cell lung cancer a bit of an edge in progression free survival -- the trial's primary endpoint, according to Wolfram Brugger, MD, of the Schwarzwald-Baar Clinic in Villingen-Schwenningen, Germany, and colleagues.

A second multicenter phase II trial, conducted among more than 120 patients, involved the Met inhibitor MetMAb, a monoclonal antibody that binds specifically to the Met receptor on cancer cells. Met expression is associated with worse prognosis in non-small cell lung cancer.

MetMab combined with erlotinib failed to show an impact in the overall patient population, according to David Spigel, MD, director of lung cancer research for the Sarah Cannon Research Institute in Nashville, Tenn., and colleagues.

At the same time, the combination improved outcomes in the pre-specified, co-primary endpoint in patients with high levels of Met expression, Spigel reported.

In the intention to treat population, the addition of MetMAb to erlotinib had no impact. Progression free survival with erlotinib plus placebo was 11.1 weeks compared with 9.6 weeks for erlotinib plus MetMAb (P=1.09).

However, in the subset of 35 patients who had high c-Met expression and were treated with MetMAb, the progression free survival was 12.4 weeks compared with 6.4 weeks for the 30 patients with high c-Met expression treated with erlotinib plus placebo (P=0.0547).

The c-Met receptor tyrosine kinase appears to be a key factor in the development and progression of several human cancers -- making it an attractive target for intervention, scientists suggested.

"Met is an important switch in cancer cells. When turned on, it influences the growth of these cells. Importantly, Met activation has also been implicated in the resistance of lung cancers to epidermal growth factor receptor inhibitors such as erlotinib. MetMAb helps target this switch and turn it off," Spigel explained.

In Spigel's study, 128 patients with advanced non-small cell lung cancer were randomly assigned to treatment with erlotinib plus placebo or erlotinib plus MetMAb. All the participants were tested for Met expression.

"In those patients who were found to express the Met protein (the target of MetMAb), MetMAb appeared to improve the treatment benefit when added to erlotinib compared with erlotinib alone," Spigel said in is oral presentation.

Conversely, patients whose tumors did not express the Met protein appeared to do worse when treated with the MetMAb/erlotinib combination. "The reasons for this finding are unclear," Spigel told MedPage Today during a press briefing. "It is possible that MetMAb may interfere with erlotinib's activity in these patients, but further study would be necessary to better understand this potential negative association," Spigel said.

In the randomized trial of ARQ, 84 patients were assigned to receive ARQ plus erlotinib and 83 patients were assigned to erlotinib and placebo.

Brugger said his trial showed that the ARQ erlotinib combination was well tolerated and there was a statistically significant difference in progression free survival, after adjustment to correct for imbalances in statistical analyses.

When researchers examined non-squamous cell cancers, the impact of ARQ also appeared to improve outcomes, Brugger added.

A discussant of the two trials, Luis Paz-Ares, MD, PhD, chief of service at Oncología Médica Hospital, Universitario Virgen del Rocio, Seville, Spain, said, "The ARQ study is interesting and the MetMAb study may be more interesting."

Paz-Ares suggested the outcomes in the subset analyses in the trials may point the way toward more personalized treatment of non-small-cell-lung cancers.

The studies were sponsored by ArQule, Inc. or Genentech.

Brugger had no financial disclosures. Other authors are employees or consulted for ArQule/Daiichi.

Spigel disclosed he is a non paid consultant for Genentech. Other authors include Genentech employees.

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